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Editorials
ulation of committed progenitors, making a fair amount of BCR-ABL RNA (and protein), die quickly, followed by a population of cells less active with regards to BCR-ABL production.
Second, the BCR-ABL decline appears to be more sig- nificant in the case of patients with the b14a2 transcript, rather than the shorter b13a2 transcript. This has been seen before in other studies.15,16 The reason is unclear, but the speculation is that the exon responsible for the longer version is immunogenetic. CML is well-known to be unusually susceptible to immune-mediated attack (note the effects of interferon, allogeneic transplant, and donor lymphocyte infusions), and the current speculation is that this is another manifestation of this effect.17 If so, we might expect the b14a2 cases to also enjoy more success with discontinuation.
Third, in multiple cases, DNA detected residual disease whereas RNA did not. Thus, in 86 cases where BCR-ABL was undetected by RNA, the DNA assay found disease in 42 (49%). Moreover, the median level of detectable dis- ease after 12 months of therapy was higher by DNA than by RNA.
Where will this lead? First, one could imagine the study of colonial heterogeneity. It is becoming clear that in many diseases (e.g. acute myeloid leukemia) there are multiple related clones at diagnosis, and treatment may cause a Darwinian selection of resistance. Since resistance is less common in CML in the TKI era, and since our tools of defining disease are insensitive to measuring the subtle difference (the Ph and BCR-ABL RNA), DNA-based assays that identify different unique BCR and ABL break- points may be able to eventually detect multiple clones. Moreover, DNA-based assays may help distinguish those patients who can and those who should not undergo dis- continuation. It may be especially interesting to study cases who have BCR-ABL by DNA but do not subse- quently relapse after TKI is discontinued. Is this evidence of immunological control of residual CML? Is this assay detecting BCR-ABL DNA in lymphocytes that may not be involved in the disease process or relapse?
In order to do some of these things, better assays will be needed. The advent of single cell technologies that can perform either genotyping and transcription analysis also need to be developed, and the search for techniques that might allow both to be performed is ongoing.18 This could allow for studies of biology, heterogeneity, and response. Assay methods to quickly genotype complex DNA rearrangement structures are now FDA approved to study immunoglobulin gene rearrangements for MRD in lym- phoid malignancies, and the same approach could be used to streamline the DNA approach in CML. New sequencing methods can detect single base pair differ- ences at a one in a million resolution, approximately 3-4 orders of magnitude better than NGS.19
Believers in the theory of the “RNA world” suggest that RNA was the key to life’s first steps from primor- dial ooze to cellular creatures (alas, some have made it farther than others).20 DNA followed as a more durable
way to collect and store information. Perhaps the same evolutionary order is on tap for those researchers inter- ested in the clinical importance of molecular diagnostics in CML.
References
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haematologica | 2018; 103(12)